Direct arylation/C-H activation and other cross-coupling approaches to important biological scaffolds

Abstract

2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS) and its biosynthetic precursor 2-heptyl3-hydroxy-4(1H)-quinolone (HHQ) are known to control the biofilm formation pathway of Pseudomonas aeruginosa. The syntheses of these signalling molecules was the first component of this work. HHQ also acted as a scaffold for the preparation of novel derivatives which represent a potential new class of antimicrobial agent. Subsequently, novel N-alkyl-4-hydroxy-2(1H)-quinolone derivatives were prepared as biological mimics of the previously mentioned 4(1H)-quinolones. Also, procedures for the synthesis of the recently proposed Pseudomonas signalling molecule 2-(2-hydroxyphenyl)thiazole-4-carbaldehyde (IQS) and analogues thereof were developed. Underlying this work was the use of palladium-catalysed aryl coupling, with particular focus on direct arylation. A synthesis of novel tricyclic isochromene products was also developed from common 1,3-diketone substrates by application of Pd-catalysed coupling. A significant amount of work was also carried out to determine mechanistic details of the key transformation.